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Substituted imidazolylmethyl pyridine and pyrazine derivatives GABAA receptor ligands

a technology of imidazolylmethyl pyridine and pyrazine derivatives, which is applied in the direction of heterocyclic compound active ingredients, biocide, drug compositions, etc., can solve the problems of compound known to exhibit a number of unwanted side effects

Inactive Publication Date: 2006-01-03
NEUROGEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0022]Within other aspects, the present invention provides methods for potentiating a therapeutic effe

Problems solved by technology

While benzodiazepines have enjoyed long pharmaceutical use as anxiolytics, these compounds are known to exhibit a number of unwanted side effects.

Method used

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  • Substituted imidazolylmethyl pyridine and pyrazine derivatives GABA<sub>A </sub>receptor ligands
  • Substituted imidazolylmethyl pyridine and pyrazine derivatives GABA<sub>A </sub>receptor ligands
  • Substituted imidazolylmethyl pyridine and pyrazine derivatives GABA<sub>A </sub>receptor ligands

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Representative Imidazolylmethyl Pyridines

[0126]This Example illustrates the synthesis of 2-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-yl methyl]-3,5-diethoxy-pyridine (compound 4), a representative imidazolylmethyl pyridine.

1. Preparation of 3,5-Diethoxy-pyridine-2-carboxylic acid ethyl ester

[0127]3,5-dibromo-pyridine-2-carboxylic acid methyl ester is prepared using published protocols (Bull. Chem. Soc. Japan (1970) 43:3210–3214), as summarized above. To a stirred solution of Na (78 mg, 3.39 mmol) in EtOH (5 mL), 3,5-dibromo-pyridine-2-carboxylic acid methyl ester (0.5 g, 1.69 mmol) is added, and refluxed for 5 hours. After evaporation of most of the solvent under reduced pressure, the residue is neutralized with saturated NH4Cl solution, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated. The organic residue is purified with 50% EtOAc / hexanes to afford 3,5-diethoxy-pyridine-2-carboxylic acid ethyl ester as a viscous liquid (250 mg, 60%); 1H NMR ...

example 2

Preparation of Representative Imidazolylmethyl Pyrazines

[0131]This Example illustrates the synthesis of representative imidazolylmethyl pyrazines.

A. 2-[2-(6-Fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-3-methoxy-5-phenyl-pyrazine (Compound 1)

1. Preparation of 3-Methoxy-5-phenyl-pyrazine-2-carboxylic acid methyl ester

[0132]To a solution of 2-amino-malononitrile 4-toluenesufonate (5.0 g, 19.3 mmol) in methanol (60 mL) at room temperature under N2 is added NaOMe (25% w / w in MeOH, 5.2 mL, 22.7 mmol). After 2 hours, acetic acid (0.204 g, 3.4 mmol) is added. The mixture is cooled to 0° C. and to the mixture is added benzaldehyde (3 g, 19.9 mmol). The mixture is stirred at this temperature for an additional 2 hours and then gradually warmed to room temperature overnight. To the mixture is added concentrated HCl (9.2 g, 80 mmol) and the mixture is stirred at room temperature over the weekend. Solvent is removed in vacuo. To the crude mixture is added saturated NH4Cl (50 mL) and DCM (100 mL). ...

example 3

Ligand Binding Assay

[0163]The high affinity of compounds of this invention for the benzodiazepine site of the GABAA receptor was confirmed using a binding assay essentially described by Thomas and Tallman (J. Bio. Chem. (1981) 156:9838–9842, and J. Neurosci. (1983) 3:433–440).

[0164]Rat cortical tissue was dissected and homogenized in 25 volumes (w / v) of Buffer A (0.05 M Tris HCl buffer, pH 7.4 at 4° C.). The tissue homogenate was centrifuged in the cold (4° C.) at 20,000×g for 20 minutes. The supernatant was decanted, the pellet rehomogenized in the same volume of buffer, and centrifuged again at 20,000×g. The supernatant of this centrifugation step was decanted and the pellet stored at −20° C. overnight. The pellet was then thawed and resuspended in 25 volumes of Buffer A (original wt / vol), centrifuged at 20,000×g and the supernatant decanted. This wash step was repeated once. The pellet was finally resuspended in 50 volumes of Buffer A.

[0165]Incubations contained 100 μl of tissue ...

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PUM

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Abstract

Substituted imidazolylmethyl pyridine and pyrazine derivatives that bind to GABAA receptors are provided. Such compounds may be used to modulate ligand binding to GABAA receptors in vivo or in vitro, and are particularly useful in the treatment of a variety of central nervous system (CNS) disorders in humans, domesticated companion animals and livestock animals. Compounds provided herein may be administered alone or in combination with one or more other CNS agents to potentiate the effects of the other CNS agent(s). Pharmaceutical compositions and methods for treating such disorders are provided, as are methods for using such ligands for detecting GABAA receptors (e.g., receptor localization studies).

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority from U.S. Provisional Application 60 / 379,117, filed May 8, 2002 which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION[0002]This invention relates to substituted imidazolylmethyl pyridine and pyrazine derivatives. More specifically, it relates to such compounds that bind with high selectivity and / or high affinity to GABAA receptors. The invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in the treatment of central nervous system (CNS) diseases.BACKGROUND OF THE INVENTION[0003]The GABAA receptor superfamily represents one of the classes of receptors through which the major inhibitory neurotransmitter, γ-aminobutyric acid, or GABA, acts. Widely, although unequally, distributed throughout the mammalian brain, GABA mediates many of its actions through a complex of proteins called the GABAA receptor, which causes alteration ...

Claims

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Application Information

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IPC IPC(8): A61K31/4965C07D403/00A01N43/40A61K31/44C07D401/00A61K31/4439A61K31/444A61K31/497A61K45/06A61P43/00C07D401/14C07D403/14C07D417/14C12N5/07C12N5/071
CPCA61K31/4439A61K31/444A61K31/497A61K45/06C07D401/14C07D403/14C07D417/14A61K2300/00A61P25/00A61P25/20A61P25/22A61P25/24A61P25/28A61P43/00
Inventor XIE, LINGHONGGHOSH, MANUKAMAYNARD, GEORGE
Owner NEUROGEN
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